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Short description of key information on bioaccumulation potential result: In rat as well as in human studies CaNa2EDTA and Na2EDTA is poorly absorbed from GI tract and the absorbed part rapidly excreted by urine, therefore one can rule out any danger of bioaccumulation. However, administration of EDTA salts results in an increased excretion of necessary ions like Zn, Mn or Ca. Short description of key information on absorption rate: CaNa2EDTA does not penetrate the skin.

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Additional information

No studies on the toxicokinetics of edetic acid are available. However, several studies have been performed using CaNa2EDTA or Na2EDTA. According to the dissociation equilibrium of edetic acid, administration of different sodium salts will result in the formation of various anionic species of EDTA in dependence on the intestinal pH value. In whatever salt EDTA is administered it is likely to chelate metal ions in vivo. Therefore the studies using CaNa2EDTA have been used as read-across. It can be assumed that the systemic absorption from the intestinal tract is low. The obtained data can be used to predict that dermal absorption should be even lower. Additionally absorbed EDTA does not undergo any biotransformation and is excreted unchanged.

In toxicokinetics studies on humans as well as rats the CaNa2 and Na salts of EDTA are poorly absorbed from the gastrointestinal tract (2 -18% in rats; less than 5% in humans) CaNa2EDTA does not penetrate the skin, only 0.001% were absorbed within 24 h of administration. Intravenously applied EDTA is rapidly excreted in urine (humans 50% within the first hour 98% within 24 h; rats: 95%- 98% within 6 h).

These data were also confirmed by the independent evaluation of the MAK Commission for the Investigation of Health Hazards of Chemical Compounds in the work area (MAK, 46. Lieferung, 2009).

Discussion on bioaccumulation potential result:

In a study conducted by Foreman et al. (1953), 50 mg/kg bw of 14C labeled calcium salt of EDTA were administered to rats orally (gavage), intraperitoneally, intravenously or intramuscularly. After oral application calcium EDTA was poorly absorbed from gastrointestinal tract (2 - 18% within 24 h). Most of the administered dose was excreted by feces 80 - 95% and much less in urine (2 -18%). After parenteral application 95 - 98% (iv: 96.09%; ip: 98.67%; im: 95.35%) of the radioactivity was excreted in urine within 6 h after application, while less than 0.1% was exhaled as CO2. At this time point non of the tissues contained more than 0.5% of the radioactivity administered.

Two additional studies on the toxicokinetics of CaNa2EDTA after i.p. application are available. In one study rats got 10 injections of 300 - 436 mg/kg bw/day 14 C labeled CaNa2EDTA. 66 - 92% of the administered dose were recovered in urine while generally less than 5% were excreted in feces. 24 h after the last injection kidneys showed less than 0.1% of the radioactivity (Doolan, 1967). In the other study, 18 rats got a single i.p. application of 400 mg/kg bw 14[C]CaNa2EDTA. Within 22 h 80% of the radioactivity were excreted in urine, while the concentration in kidney homogenate was approximately 0.1 - 0.2% during this time period (Miller, 1986).

The effects of sc application of CaNa2EDTA on Zn, Cu and Mn metabolism were investigated in female dogs. CaNa2EDTA was applied with a dose of 280 mg/kg bw/ every 6 hours for 54 h. Urine was collected every 6 h and the Zn, Cu and Mn content analysed. CaNa2EDTA application increased the urinary excretion of Zn, Cu and Mn significantly (Ibim, 1992).

In addition in poorly documented studies by Yang (1964) the toxicokinetics of Na2EDTA was analysed in rats. After gavage application of 47.5, 95 and 142.5 mg/kg bw the amount of EDTA ingested was proportional to the amount of urinary excretion with a peak excretion 4 h after application. After gavage administration of 400 mg/kg bw to weanling and adult rats roughly 90% of the dose were recovered in feces, while only 5.3 % (adults) - 8.6 % (weanlings) were recovered in urine within 48 h. It was therefore assumed that most of the orally applied EDTA is not absorbed. After a single gavage application of ca. 475 mg/kg bw to rats, the gastrointestinal tract was removed in intervals up to 32 h and the EDTA content analysed. All EDTA passed through the stomach within 12 h and 93% of the dose was recovered in the colon after 32 h, which demonstrated a poor absorption from GI tract. The EDTA contents of the small intestine and urine reached a maximum about 4 h after dosage. Urinary excretion over the period of 32 h cumulated to 6% of the dose. In an additional study Yang stated that of a dietary dose of 300, 600 and 3000 mg/kg bw 82%, 44% and 45% could be recovered in urine and feces. However, it is unclear were the residual percentage of Na2EDTA remained.

Foreman & Trujillo (1954) studied the toxicokinetics of 14C-CaNa2EDTA in young, healthy male volunteers. 4.2 mg test substance per person were applied i.v. or i.m. 50% of the dose was excreted in urine within 1 h (i.v.) or 2.5 h (i.m.). Within 24 h >98% of the dose were excreted in urine after both applications. The half-live blood clearance was 1 h 5 min (i.v.) or 1.5 h (i.m.) respectively. Additionally, Foreman & Trujillo administered 14C-CaNa2EDTA orally at a dose of 1.5 mg/person. CaNa2EDTA was poorly absorbed from gastrointestinal tract. Within 72 h 91% of the dose were excreted in feces and 4.2% in urine. No test substance could be detected in blood.

Discussion on absorption rate:

In a study on young, healthy, male volunteers, Foreman & Trujillo (1954) investigated the dermal absorption of CaNa2EDTA. 3 mg of a mixture of 14C labeled and unlabeled substance was prepared in water soluble base (resulting paste was applied over an area of 100 cm² for 24 h under occlusive conditions). In one test, the Na salt was used instead of Ca salt. The maximum activity in the urine was 0.001% of the administered dose.